Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties.

A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01-0.03 mg/kg.

Design and Synthesis of Novel and Selective Glycine Transporter-1 (GlyT1) Inhibitors with Memory Enhancing Properties.

We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo[3,4- c]pyrazoles amides (21-50) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound 46, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg.

Lateralized swim positions are conserved across environments for beluga (Delphinapterus leucas) mother-calf pairs.

Research with wild belugas has indicated that, during mother-calf swims, calves spend more time on their mothers' right side, which enables the calves to maintain visual contact with their mothers using their left eye. This bias may facilitate processing of social information by the right hemisphere, much like human and non-human primates and other animals. The current study explored the social laterality of the Cook Inlet, AK beluga population in comparison to a beluga population in managed care. As expected, the results indicated that the calves spent more time on the mothers' right side than the left for both populations. We also examined the developmental trend for the belugas in managed care and found that the calves generally preferred to swim on their mother's right side across most months, although there was an inversion during the third quarter when a left-side preference appeared. Individual differences were present. The results corroborate previous research conducted with two wild beluga populations from the White Sea and from the Sea of Okhotsk in which a left-eye bias was displayed by calves when swimming with their mothers. In conclusion, a preference for a lateralized swim position appears to be conserved across wild and managed care settings, and this lateralized swim position may facilitate the processing of social information or familiar stimuli for the calves.

Simultaneous quantification of davalintide, a novel amylin-mimetic peptide, and its active metabolite in beagle and rat plasma by online SPE and LC-MS/MS.

BACKGROUND: Davalintide, an investigational therapeutic peptide for the treatment of obesity, is rapidly metabolized by enzymatic cleavage of its N-terminal lysine residue to produce an active des-Lys metabolite in vivo. While a sensitive ELISA assay is available, it is unable to distinguish davalintide from its metabolite. Consequently, we developed an online SPE-LC-MS/MS method for simultaneous quantification of the drug and its active metabolite in beagle and rat plasma samples and compared the resulting pharmacokinetic profiles with those determined by ELISA. RESULTS: The total concentration of active drug measured by ELISA correlated well with the total concentration of davalintide and its metabolite using online SPE-LC-MS/MS. CONCLUSION: The technique is a viable alternative to immunochemistry-based methods for peptide quantitation in terms of sensitivity, reproducibility and specificity, and importantly, does not require developing antibody-based reagents.